The efficacy of therapeutic granulocyte transfusions is limited by the relatively small number of cells obtained using standard starch and steroid stimulation of the donor. To determine an optimal mobilization schedule that would maximize cell yields and minimize donor discomfort during granulocytapheresis, we designed a pair-controlled study of three mobilization schedules. Twenty healthy donors underwent three leukapheresis procedures each, receiving either dexamethasone (8 mg orally 12 hrs prior to donation), G-CSF (5 microgram/kg SQ 16-24 hrs prior to apheresis), or dexamethasone plus G-CSF (D+G in the same doses). Seven liters of whole blood were processed on the CS-3000 Plus device using hetastarch as the sedimenting agent. All products were transfused to patients with qualitative or quantitative granulocyte deficiencies and life-threatening infections. Administration of G-CSF alone led to a 3.5-fold increase and the combination of dexamethasone plus C-CSF led to a 4.8-fold increase in donor peripheral blood granulocyte counts compared with dexamethasone alone (from 6.0 + 2.3 with dexamethasone, to 21.3 + 5.2 and 28.9 + 6.8 x109 cells/L with G-CSF and D+G, respectively). Similarly, use of G-CSF alone or the combination of dexamethasone and G-CSF resulted in 2.4- and 3.4-fold increases in granulocyte content in the product compared with dexamethasone alone (from 2.16 +0.71 with dexamethasone alone to 5.08 + 1.10 and 7.25 + 1.54 x1010 cells total with G-CSF and D+G, respectively), p <0.01 for all comparisons between dexamethasone and either G-CSF or D+G. In addition, both peripheral blood and product granulocyte counts were greater (p <0.05) when donors took combination D+G vs G-CSF alone (36% increase in the blood granulocyte count and 43% increase in product granulocyte content when dexa was added to G-CSF). With dexa alone, 25% of donors had insomnia or flushing; with G-CSF, 65% had bone pain, headache, insomnia, fatigue, or diaphoresis; this increased to 85% with combination D+G. Two donors requested discontinuation of G-CSF-mobilized donations due to the discomfort and inconvenience of the mobilization regimen. Addition of dexamethasone to G-CSF significantly increases granulocyte yields at the expense of a moderate increase in donor inconvenience and discomfort The availability of granulocytapheresis products with markedly increased numbers of highly functional cells is likely to result in a resurgence of interest in this transfusion component.